The mechanisms through which testosterone (T) stimulates the display of male-typical aggressive behavior remain controversial. At the center of this issue is the necessity for defining the role of the androgenic and estrogenic metabolites of T in the promotion of fighting behavior. To address this fundamental question about hormone action in the central nervous system, a research strategy that integrated behavioral and biochemical studies of mice from a number of different strains was recently employed. Genotypic differences in responsiveness to the aggression-promoting property of androgen and estrogen were found among male mice from the CF-1, CFW, and CD-1 strains. These differences in sensitivity appeared to be related to genetically determined differences in receptor binding. More specifically, responsiveness to estrogen (as measured with diethylstilbestrol, DES) was related to either a higher number of binding sites or higher affinity binding between DES-estrogen receptor. The binding of DHT, an androgen that was moderately effective in promoting aggression in the 3 strains, was not systematically related to its behavioral effects. The goal of the proposed series of experiments will be to further explore the relationship between receptor binding and behavioral responsiveness through the use of integrated behavioral and biochemical investigations. The studies will determine whether the relationship between K/d, B/max, and sensitivity to the aggression-promoting property of DES can be extended to other estrogens and androgens or whether additional aspects of receptor binding (dissociation kinetics, nuclear binding) should be examined to identify the molecular correlates of behavioral responsiveness to these hormones. In addition, the role of neonatal hormonal stimulation is establishing the biochemical basis for behavioral responsiveness later in life will also be examined. The studies are expected to support the hypothesis of a relationship between receptor binding and responsiveness to the aggression-promoting property of androgen and estrogen. Such findings would significantly enhance our understanding of the molecular processes involved in the hormonal regulation of intermale aggressive behavior in mice and may facilitate the development of a theoretical model of steroid sensitivity in neural tissues that can be assessed in future investigations.